Lung cancer is the leading cause of cancer deaths in the US and worldwide. Given its prevalence, morbidity and mortality, it is clear that in terms of treatment, the lung cancer problem is far from solved; and that new agents are urgently needed. Our preliminary data indicate that the novel compound phospho-sulindac (PS) is potentially highly effective against lung cancer. Our hypothesis is that PS is a safe and highly effective agent against lung cancer. To evaluate this hypothesis, we propose the following specific aims: 1) Determine the efficacy and mechanism of action of PS in animal models of lung cancer. PS will be administered to nude mice with xenografts of human lung cancer cells representing the major clinical subcategories and to nude rats with orthotopic xenografted lung cancer and assess the in vivo changes of the signaling pathways already outlined. 2) Perform toxicity studies of PS. We will determine the genotoxicity, maximum tolerated dose and repeated dose/organ toxicity of PS. 3) Study the metabolism, pharmacokinetics and pharmacodynamics of PS. These aims will assess parameters that are essential to the preclinical development of PS: drug efficacy; drug safety; drug metabolism; pharmacokinetics; and pharmacodynamics. The expected results will pave the way towards the completion of PS's preclinical evaluation. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the US and worldwide. Given its prevalence, morbidity and mortality, it is clear that in terms of treatment, the lung cancer problem is far from solved and that new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, which is potentially highly effective against lung cancer. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.